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Papers of the Week

2019 Jul 10

J Neurosci



Myelinating glia-specific deletion of Fbxo7 in mice triggers axonal degeneration in the central nervous system together with peripheral neuropathy.


Joseph S, Vingill S, Jahn O, Fledrich R, Werner HB, Katona I, Möbius W, Mitkovski M, Huang Y, Weis J, Sereda MW, Schulz JB, Nave K-A, Stegmüller J
J Neurosci. 2019 Jul 10; 39(28):5606-5626.
PMID: 31085610.


Myelination of axons facilitates the rapid propagation of electrical signals and the long-term integrity of axons. The ubiquitin-proteasome system (UPS) is essential for proper protein homeostasis, which is particularly crucial for interactions of post-mitotic cells. In our study, we examined how the E3 ubiquitin ligase FBXO7-SCF (SKP1, Cul1, F-box protein) expressed in myelinating cells affects the axon-myelin unit. Deletion of in oligodendrocytes and Schwann cells in mice using the Cnp1- driver line led to motor impairment due to hind limb paresis. It did not result in apoptosis of myelinating cells, nor did it affect the proper myelination of axons or lead to demyelination. It however triggered axonal degeneration in the central nervous system (CNS) and resulted in the severe degeneration of axons in the peripheral nervous system (PNS), inducing a full-blown neuropathy. Both the CNS and PNS displayed inflammation, while the PNS was also characterized by fibrosis, massive infiltration of macrophages, and edema. Tamoxifen-induced deletion of after myelination using the Plp1- line, led to a small number of degenerated axons and hence a very mild peripheral neuropathy. Interestingly, loss of also resulted in reduced proteasome activity in Schwann cells but not in cerebellar granule neurons, indicating a specific sensitivity of the former cell type. Taken together our results demonstrate an essential role for FBXO7 in myelinating cells to support associated axons, which is fundamental to the proper developmental establishment and the long-term integrity of the axon-myelin unit.The myelination of axons facilitates the fast propagation of electrical signals and the trophic support of the myelin-axon unit. Here, we report that deletion of in myelinating cells in mice triggered motor impairment, but had no effect on myelin biogenesis. Loss of Fbxo7 in myelinating glia however led to axonal degeneration in the central nervous system and peripheral neuropathy of the axonal type. In addition, we found that Schwann cells were particularly sensitive to Fbxo7 deficiency reflected by reduced proteasome activity. Based on these findings, we conclude that Fbxo7 is essential for the support of the axon-myelin unit and long-term axonal health.